Interview Rucaparib shows its efficacy in advanced pancreatic cancer harboring BRCA1, BRCA2 or PALB2
Among 42 evaluable patients, the 6-month progression-free survival (PFS) rate was 59.5% (95% CI, 44.6% -74.4%). The median PFS obtained with this approach was 13.1 months (95% CI, 4.4-21.8), while the median overall survival (OS) was 23.5 months (95% CI, 20 -27). At 12 months, the PFS rate was 54.8% (95% CI, 39.7% -69.9%).
Among 36 patients with measurable disease, maintenance rucaparib induced an objective response rate (ORR) of 41.7% (95% CI, 25.5% -59.2%); this included 3 complete responses (CR) and 12 partial responses. The median duration of response (DOR) was 17.3 months (95% CI, 8.8-25.8). In addition, the disease control rate (DCR) was 66.7% (95% CI, 49.0% to 81.4%). Responses were observed in 41% (n = 11/27) of patients with BRCA2, 50% (n = 3/6) of people with a germline PALB2, and 50% (n = 1/2) of those with BRCA2 pathogenic variants.
“This is another step forward for PARP inhibitors and for the treatment of difficult-to-treat pancreatic tumors,” said Kim Reiss, MD, lead author of the study and assistant professor of hematology-oncology at the Perelman School of Medicine of Penn Medicine. A press release.2 “It’s a safe option that has the potential not only to sustain responses, but also to shrink pancreatic tumors and, in some cases, achieve CRs for people with these mutations.”
Patients with pancreatic cancer who harbor pathogenic variants such as BRCA1, BRCA2, or PALB2 have been shown to be very sensitive to treatment with platinum-based chemotherapy. In May 2020, the PARP inhibitor olaparib (Lynparza) has been approved by the FDA as a maintenance treatment for patients with metastatic platinum-sensitive pancreatic adenocarcinoma that hosts a germ line BRCA1 and BRCA2 pathogenic variants.
However, efforts are now being made to expand the group of pancreatic cancer patients who can potentially benefit from PARP inhibitors, beyond those who harbor a germline. BRCA pathogenic variants. In addition, researchers are seeking to refine clinical and biological biomarkers that could predict the benefit of these agents in patients with this disease.
In the phase 2 trial, researchers investigated whether maintenance treatment with rucaparib in patients with advanced platinum-sensitive pancreatic cancer and a germline or somatic pathogenic variant in one or the other BRCA1, BRCA2, or PALB2, could induce a rate of PFS at 6 months of at least 60%.
The open-label, single-arm, single-stage, phase 2 trial included patients 18 years of age or older with locally advanced or metastatic pancreatic cancer, and confirmed or somatic germline or somatic variants. probable germline BRCA1, BRCA2, or PALB2.
Initially, patients had to have received at least 16 weeks of treatment with platinum-based chemotherapy without showing evidence of resistance to platinum, but the study protocol was modified to allow patients who had a contraindication to treatment platinum to register without prior exposure. Additional eligibility criteria required that patients have acceptable organ function, an ECOG performance index of 0 or 1, and a life expectancy of at least 12 weeks. In particular, those who had already received a PARP inhibitor were excluded.
Study participants received oral rucaparib as monotherapy at a twice daily dose of 600 mg on days 1-28 of each 28-day cycle until disease progression or intolerable toxicity. The primary endpoint of the study was the rate of PFS at 6 months, while the secondary endpoints included safety, ORR, DCR, DOR, and OS.
Among the 42 evaluable patients enrolled in the study, the median age at diagnosis was 61.5 years (35 to 81 years) and more than half, or 57%, were female. In terms of pathogenic variants, 64% had a germline BRCA2 mutations (n = 27), 17% had a germline BRCA1 mutations (n = 7), 14% had a germline PALB2 mutations (n = 6), and 5% had BRCA2 mutations (n = 2). The median time from diagnosis to start of study was 5.6 months (range 2.5 to 62.5). Eighty-six percent of patients had measurable disease (n = 36) and 95% had metastatic disease at the start of the study (n = 40).
In addition, 34 patients had received 16 weeks or more of platinum therapy (range, 0-139), while 6 patients had received less than 16 weeks due to either intolerance (n = 5) or allergy (n = 1) to platinum. Notably, 2 participants had severe neuropathy due to previous exposure to nab-paclitaxel (Abraxane) and they entered the study without receiving platinum treatment.
At the time of the data cutoff, 66.6% of patients had progressed (n = 28) and 47.6% had died (n = 20).
Additional data indicated that patients BRCA2 mutations had longer PFS with maintenance rucaparib than those with BRCA1 mutations, at a median of 18 months (95% CI, 12.0-23.9) vs 3.7 months (95% CI, 0-8.6), respectively (P = .002). In the 6 patients with PALB2 mutations, the median PFS with rucaparib was 14.5 months (95% CI, 0.7-28.3).
No significant difference in OS was observed between subgroups of patients with BRCA2 and BRCA1; here, the median OS was 25.3 months (95% CI, 19.8-30.7) vs 14.5 months (95% CI, 12.8-16.2), respectively (P = 0.34).
In addition, among 36 patients with measurable disease, the median PFS with maintenance rucaparib was 7.5 months (95% CI, 0.0-20.0), while the median OS was 23.1 months (95% CI, 18.4-27.2). In 6 patients without measurable disease, the PFS and median OS were not achieved (P = 0.09, for each).
When disaggregated by pathogen variant, the ORR with maintenance rucaparib was 40.7% in people with a germline BRCA2 mutations (n = 11/27), 50.0% in those with a germline PALB2 mutations (n = 3/6), 50.0% in those with BRCA2 mutations (n = 1/2), and 0% in those with a germline BRCA1 mutations (n = 0/7). Notably, a response was noted in a patient with squamous cell carcinoma of the pancreas as part of a germ line PALB2 pathogenic variant.
The most common adverse reactions (ADRs) seen with rucaparib included anemia (74%), nausea (48%), increased alanine aminotransferase (ALT; 47%), fatigue (45%) , thrombocytopenia (39%) and dysgeusia (37%). However, most of the reported AEs were severity 1 or 2.
The most common grade 3 AEs included anemia (22%), fatigue (4%), increased ALT (4%), thrombocytopenia (4%), nausea (2%), vomiting (2%) and the decrease in the number of white blood cells (2%). Additionally, 15 patients required temporary dose suspensions due to toxicities, 9 patients required dose reductions due to AEs, and 1 patient withdrew study consent due to grade fatigue. 3. However, no other patient discontinued treatment due to AEs and no Grade 4 AEs were reported.
“These latest results show us another effective and less toxic maintenance treatment option for [patients with] pancreatic cancer, and underscore the importance of counseling and genetic testing, which can potentially steer treatment in a better direction, ”added study author Susan Domchek, MD, executive director of the Basser Center for BRCA at Penn Medicine, in the press release. .
- Reiss KA, Mick R, O’Hara MH et al. Phase II maintenance study of rucaparib in patients with advanced platinum-sensitive pancreatic cancer and a pathogenic germline or BRCA1, BRCA2, or PALB2. J Clin Oncol. Published online May 10, 2021. doi: 10.1200 / JCO.21.00003
- A break from chemotherapy: The PARP inhibitor shrinks tumors in pancreatic cancer patients with mutations. Press release. Penn Medicine. May 10, 2021. Accessed May 12, 2021. https://bit.ly/2QdvGGh